DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 5/08/2026 to claims 1, 3, and 20 have been entered. Claims 2, 5, 19, 21, 23-28, and 30-32 are canceled. Claims 36 and 37 have been added. Claims 1, 3, 4, 6-18, 20, 22, 29, and 33-37 remain pending, and are being considered on their merits. References not included with this Office action can be found in a prior action.
The instant amendments to claim 1 have overcome the 35 U.S.C. § 112(b) rejections of record, which are withdrawn.
Applicant’s arguments on page 8 of the reply are found persuasive, and the nonstatutory double patenting rejections of record are withdrawn.
Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 4, 6-18, 20, 22, 29, and 33-37 are rejected under 35 U.S.C. 103 as being unpatentable over Hiller et al. (US 2019/0031997; provided in the IDS dated 8/25/2025).
Hiller teaches a method for culturing cells to produce a recombinant protein, comprising: 1) initiating a culture in a bioreactor at a culture volume that is at least 50% of the final bioreactor working volume (Example 2 at ¶0080), 2) inoculating the culture with CHO cells engineered to express the recombinant IgG antibody (Example 2, the title of this subheading just before ¶0080, and noting antibody production at Fig. 20 and ¶0101), 3) perfusing the culture at one or more perfusion rates of less than or equal to 0.5 culture volumes/day (V/d) until the culture reaches one or more desired target criteria (Example 2, at Fig. 12 with the V/d being less than 0.5 for days 1-2 of culture and the target criteria being protein concentration at about 50-100 mg/L as set forth in Fig. 20), 4) increasing the culture volume to a final culture volume (Example 2 at ¶0080 and noting being operated a similar volume ration as Example 1, and ¶0067 wherein transferring about 19% of the volume of the initial/starting N-1 perfusion bioreactor to the second/final production CSTR bioreactor), and 5) once the final culture volume is achieved, perfusing the culture at one or more perfusion rates of less than or equal to 0.5 culture volumes/day (V/d) for less than 5 days in the N-1 bioreactor (Example 1, at ¶0068 and Fig. 3), reading in-part on claim 1 and reading on claims 33 and 35. IN a separate embodiment, Hiller teaches a 1:1 volume ratio between the culture bioreactor and the production/CSTR bioreactor of 1:1 (¶0054), reading on the culture volume that is at least 50% relative to any final/production bioreactor working volume of claim 1 and reading in-part on claim 3. Hiller teaches daily average perfusion rates (i.e. RV/day) of 1.76 or 3.6 depending upon the target criteria of 80 x 106 cells/ml or 40 x 106 cells/ml in the N-1 bioreactor (Fig. 12, ¶0025, and ¶0085), reading in-part on the second perfusing step of claims 1, and reading in-part on claims 11 and 12, 17, and 18. Hiller teaches that the cells control and ramp up their own perfusion rate and simultaneous removal of cell-free permeate as a function of the pH of the cell culture media (¶0085) and a set predetermined pH value being 7 or in the range of 6.8-7.4 (¶0071), reading in-part on the second perfusing step of claims 1, reading in-part on claims 11, 12, 17, and 18, and reading on the differential perfusion and associated generic feed and permeate rates of claims 16 and 20. Hiller teaches a cell bleed rate for the N-1 bioreactor of 0.4 volumes removed per day (¶0068), equating to the 60% working volume of claims 3 and 20. Hiller teaches an initial cell density of 1.2 x 106 cells/ml in the N-1 bioreactor (Table 5), reading on claim 4. Hiller teaches wherein the bioreactor is operated in batch mode for up to 24 hours following inoculation (Fig. 12, noting a zero perfusion on day 1 and non-zero perfusion rate on day 2, and ¶0085, noting the N-1 bioreactors are initially operated only in batch mode without perfusion), reading on claim 6. Hiller teaches that wherein the culture is in a growth phase prior to the increase in culture volume to the final culture volume (e.g. exponential growth in the N-1 bioreactor at days 1-5), reading on claim 7 and the embodiment of exponential growth for days 1-3 (i.e. 24-72 hours) post-inoculation for claim 15. Hiller teaches the duration of the growth phase is less than or equal to 60% of the culture duration; and/or the culture temperature during the growth phase is 35°C to 37°C (Table 5 for a culture temperature of 36.5 °C, and Fig. 2A for the growth phases being the exponential increase in viable cell density being the first 5 days for the N-1 bioreactor (the white squares) and the first 6 days for the CSTR bioreactor (the black squares), reading on claims 8 and 10, the CSTR bioreactor as the production reactor for claim 9, and claim 22. Hiller teaches a target criteria comprising a cell density of 100-350 x 105 cells/ml (i.e. 10-35 x 106 cells /ml) (Fig. 2A, the CSTR bioreactor (the black squares) starting at about day 20), reading on claims 13 and 14. Hiller teaches harvest/recovery and purification of the recombinant secreted therapeutic protein by immunoaffinity or ion-exchange columns (¶0066), reading on claim 29. Hiller teaches an antibody fragment as a species of recombinant protein (¶0065), reading on claim 34. Hiller teaches glutamine synthetase-knockout CHO cells (Table 1 underneath ¶0055, i.e. CHO-K1 GS), reading on claim 36. Hiller teaches dihydrofolate reductase-knockout CHO cells (Table 1 underneath ¶0055, i.e. CHO/dhfr-), reading on claim 37.
Regarding claim 1, Hiller does not teach a second step of perfusing the culture at one or more perfusion rates of less than or equal to 0.5 culture volumes/day (V/d) until the culture is terminated or harvested. Regarding claim 3, Hiller does not teach wherein the culture is initiated at a culture volume that is 60% to 70% of the final bioreactor working volume. Regarding claim 11, Hiller does not teach wherein the culture is perfused at one or more perfusion rates of 0.05 V/d to 0.5 V/d until the culture reaches one or more desired target criteria, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same; and/or once the final culture volume is achieved, the culture is perfused at one or more perfusion rates of 0.05 V/d to 0.5 V/d until the culture is terminated or harvested, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same. Regarding claim 12, Hiller does not teach wherein the culture is perfused at one or more perfusion rates of 0.10 V/d to 0.25 V/d until the culture reaches one or more desired target criteria, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same; and/or once the final culture volume is achieved, the culture is perfused at one or more perfusion rates of 0.10 V/d to 0.25 V/d until the culture is terminated or harvested, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same. Regarding claim 17, Hiller does not teach wherein at least one of the one or more feed rates is less than or equal to 0.50 V/d and at least one of the one or more permeate rates is less than or equal to 0.20 V/d, wherein each of the one or more feed rates is greater than the contemporaneous permeate rate. Regarding claim 18, Hiller does not teach … Regarding claim 20, Hiller does not teach wherein at least one of the one or more feed rates is less than or equal to 0.40 V/d and at least one of the one or more permeate rates is less than or equal to 0.15 V/d, wherein each of the one or more feed rates is greater than the contemporaneous permeate rate.
However, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range(s) to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case and regarding claims 1, 11, 12, 17, and 18, Hiller clearly teaches that the daily average perfusion rates (i.e. RV/day) is a known result-effective variable depending upon the desired cell density in Hiller’s methods of making recombinant protein(s) from mammalian cells as cited above. Regarding claim 3, Hiller clearly teaches that a 1:1 volume ratio between the culture bioreactor and the production/CSTR bioreactor of 1:1 is result-effective to operably produce recombinant proteins in the mammalian cell culture methods as cited above. Thus, the burden is shifted back to establish criticality of the culture volumes/day range by objective evidence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 6-9 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
In response to applicant's argument on page 7 of the reply that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a single-bioreactor process) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Independent claim recites the open-ended transitional phrase “comprising”, and so does not exclude additional, unrecited elements or method steps at this time, see M.P.E.P. § 2111.03
Conclusion
No claims are allowed. No claims are free of the art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at 571-272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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